Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the U.S.A., with a five-year survival rate of 4%. It is also a major cause of mortality among the VA patient population. There is great urgency to identify new therapeutic strategies for PDAC because current treatments have little impact on patient survival. More than 90% of PDACs have oncogenic mutations in the Kras gene. The phosphoinositide 3-kinase p110? catalytic subunit (gene name Pik3ca) is a downstream effector of Kras. We previously reported that pancreas-specific ablation of Pik3ca completely protected mice from oncogenic KrasG12D-induced tumor formation. The current proposal investigates the role of Pik3ca after pancreatic tumors have formed. Invasive KrasG12D and Trp53R172H (KPC) cells orthotopically implanted in the pancreas of immunocompetent mice leads to rapid tumor progression and death of the host animal. However, when Pik3ca was silenced, implanted KPC tumors completely regressed. Surprisingly, implanted Pik3ca-null KPC tumors progressed and killed immunodeficient mice, but adoptive transfer of T lymphocytes completely protected the mice from these tumors. Therefore, we hypothesize that inhibition of Pik3ca in the tumor cells, without inhibiting PI3K signaling in the immune cells, will allow an immune-mediated regression of pancreatic cancer. In Aim 1, we will investigate the signaling pathways and genetic profiles of Pik3ca-null versus parental KPC cells to better understand the immunological changes caused by the knockout tumor cells. We will also examine the host T-cell response to better understand how pancreatic tumors evade immune surveillance. In Aim 2, we will assess the therapeutic potential of a strategy that inhibits p110? in pancreatic cancer cells without inhibiting PI3K signaling in cytotoxic T lymphocytes. Successful completion of this proposal will produce insights into PI3K-regulated mechanisms that allow PDAC to evade the immune system and progress to a deadly disease. This understanding may allow future studies to elucidate the most appropriate means of targeting Pik3ca signaling pathways in PDAC to improve therapy for this deadly cancer.